Impacts Of Adverse Maternal Enviroment On Infant Metabolic Health,Related Biomarkers And Mechanisms

Background:Adverse maternal environment can“program”the fetus,and may be the fetal origins of some chronic diseases in adulthood.Aim:To explore the impacts of adverse maternal enviroment on infant health in early life,the biomarkers and mechanisms.Methods:（1）At the population-level,based on a retrospective birth cohort in Quebec,Canada,using Aboriginal peoples as a typical exposed population to adverse maternal enviroment,we explored the disparities in infant hospitalization（an indicator of severe diseases）rates in Aboriginal vs.non-Aboriginal infants to assess the impact of adverse maternal enviroment on child health in early life.（2）At the individual-level,based on the Canadian 3D Birth Cohort and the Shanghai Birth Cohort（SBC）,using small-for-gestational-age（SGA）as a typical exposure indicator to adverse maternal enviroment,we conducted two similarly designed nested case control studies to explore the impact of SGA（<10th percenttile）on neonatal glucose metabolic health biomarkers.（3）Using maternal circulating placental growth facotor（Pl GF）and its ratio to its soluble receptor fms-like tyrosine kinase-1（s Flt-1）at 32-35 weeks of gestation,as the biomarkers of adverse intrauterine enviroment,we assessed whether they are associated with neonatal glucose metabolic health biomarkers.（4）In a matched case（SGA）control study,we used the 850k methylation microarray to detect SGA related placenta gene DNA differentially methylated sites and regions to explore the programming mechanisms.Results:（1）Infant hospitalization rates were 2 times higher in Aboriginal vs.non-Aboriginal infants.Adjusting for maternal socio-demographic characteristics,the risk disparities were narrowed but remained.（2）Compared SGA with optimal birth weight(OBW,25-75^th percentiles)infants,neonatal HOMA-β,leptin and High Molecular Weight（HMW）adiponectin concentrations were lower in the 3D Cohort,while C-peptide and HMW adiponectin concentrations were lower in the SBC cohort.（3）In the 3D cohort,SGA infants with low maternal circulating Pl GF concentrations(<25^th percentile)had lower neonatal HOMA-β,and lower cord blood leptin concentrations.In the SBC cohort,SGA infants with low maternal circulating Pl GF or high maternal circulating s Flt-1/Pl GF ratio(>75^th percentile)had lower cord blood C-peptide and HMW adiponectin concentrationsr.（4）There were 183 SGA associated placenta gene DNA differentially methylated sites and 27 regions including 10 genes（MUC5B,GALNT2,etc）enriched in the“carbohydrate metabolic process”.Conclusions:（1）Populations exposed to adverse maternal enviroment had significantly detrimental impact on child health in early life.（2）Using SGA as the typical adverse maternal environment exposure indicator at the individual level,we found that SGA infants might have impairedβ-cell function,and lower HMW adiponectin levels.（3）Maternal circulating low Pl GF or high s Flt-1/Pl GF ratio in late gestation may indicate impairedβ-cell function,decreased leptin or HMW adiponectin levels in SGA newborns.（4）SGA infants had significant changes in placenta DNA methylation profile.The genes involved in glucose metabolic homeostasis were significantly enriched in differential methylation sites,revealing that epigenetic changes are an important mechanism in the programming impact on metabolic health in the offspring.Our study is the first to reveal:1)adverse maternal environment exposures at both population and individual levels have significant adverse impacts on child health;2)SGA infants might have impairedβ-cell function;3)Maternal circulating Pl GF or s Flt-1/Pl GF ratio may have predictive values for neonatal metabolic health.The findings have provided new clues in the prevention of the detrimental impacts of adverse maternal environment on metabolic health in the offspring.